Aerosol pharmaceutical solution formulation containing glucocorticoids stable to the storage; method for stabilizing formulations and use of a stabilizer

a technology of glucocorticoids and formulations, which is applied in the direction of biocide, plant growth regulators, pharmaceutical non-active ingredients, etc., can solve the problems of inconvenient and expensive storage of glucocorticoids, chemical degradation, and inability to meet the needs of use,

Inactive Publication Date: 2005-05-05
LAB PABLO CASSARA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017] Surprisingly, the inventors of the present invention have found out interesting improvements By adding small amounts of water or a mixture of water and organic acid, more particularly a mixture of water and citric

Problems solved by technology

There has been a common difficulty in preparing these medicinal products delivering glucocorticoids because they are often chemically unstable formulated as aerosol formulations and degrade during storage.
Therefore, their storage are inconveniently limited and expensive.
Chemical degradation is especially problematic when the steroid is dissolved in the formulation and, consequently most of steroid products for inhalers have been formulated as particulate suspensions of the steroid, which are much less susceptible to chemical

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0070] The following model was adopted to illustrate the unexpected effect of the water. A solution of 150 mg of Budesonide in 50 ml of anhydrous ethanol as solvent was prepared. Then, the mixtures contained in bottle with screw tap and summarized in Table I were prepared by adding different amounts of water with and without aluminum oxide (Aldrich, Trademark, neutral, activated Brockmann I, mesh 150).

BudesonideAluminumExperiment Nosolution (ml)Water (μl)Oxide (g)1A1000.0001B101740.0001C1000.3331D101740.333

[0071] The Budesonide percentage results found after 22 hours of storage at 75° C. were the following:

Experiment NoAfter 22 hours storage1A95.41B93.51C4.91D14.7

[0072] It is important to clarify that this model is analogous to that adopted in patent U.S. Pat. No. 6,315,985 to demonstrate the negative effect of aluminum oxide on the stability of the corticoids having C-20 ketone and OH groups in carbons 17 and / or 21. Nevertheless, contrary to the assumption in that patent, the a...

example 2

[0073] Using the same model of example 1, the effect of increasing amounts of water in the stabilization of Budesonide in the presence of Aluminum oxide was investigated.

BudesonideAluminumExperiment NoSolution (ml)Water (ml)Oxide (g)2.A100.000.3332.B101740.0002.C108700.3332.D1017400.333

[0074] The Budesonide percentage results found after 20 hours of storage at 75° C. were the following ones:

Experiment NoAfter 20 hours storage2.A17.62.B29.32.C41.62.D50.6

[0075] This example demonstrates clearly that the effect of adding water is favorable to the Budesonide stabilization in the presence of Aluminum Oxide and it is opposed to the assumption in patent U.S. Pat. No. 6,315,985 mentioned in the previous example.

example 3

[0076] Based on the previous examples, aerosols containing the following formulation were prepared and tested using different commercial dispensing valves and aluminum canister without coating commonly used in aerosols inhalers.

Component% by weightBudesonide0.1722Alcohol absolute10.000Water0.2200HFA 134a89.6078

[0077] The aerosols were storage during 6 months at 40° C. and 75% of relative humidity. The total degradation percentage results were the followings:

After 3 monthsAfter 6 monthsType of valvestoragestorageValve type 12.85%5.20%Valve type 21.63%2.70%Valve type 3 3.4% 4.2%

[0078] The main difference between the valves is the composition of the rubber contained in the gum seals. In type 1, formulation is based on nitrile-rubber. Type 2 is based on thermoplastic elastomer and the one of type 3 is also based on thermoplastic elastomer with a later treatment.

[0079] Comparing the values described in example 8 and 9 of patent U.S. Pat. No. 6,315,985 that contain a similar Budesoni...

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Abstract

Aerosol pharmaceutical solution formulations containing glucocorticosteroids stabilized by adding water or a mixture of water and citric acid, avoiding corrosion of the elements of container under standard storage conditions are described. The formulations comprise: between 0.05 and 1.0% by weight of a glucocorticoid having a C-20 ketone and OH group in carbons 17 and/or 21 as active substance; between 0.10 and 3% by weight of a selected stabilizer selected between water, or a mixture of water and organic acid selected between citric acid and tartaric acid; a cosolvent in amount sufficient to solubilize the active substance; optionally a surfactant; and propellant in sufficient amount to achieve100% by weight of the finished solution. Glucocorticosteroids having a C-20 ketone and an OH group at the C-17 and/or 21 position with varying substituents, have many well-known therapeutic uses, especially based upon their anti-inflammatory activity. This types of steroids, glucocorticosteroids, and their pharmaceutical formulations are useful in the treatment of several diseases including bronchial disorders and inflammatory conditions. Preferably, the glucocorticoid is selected between Triamcinolone Acetonide, budesonide, Dexamethasone and betamethasone 17-valerate. A method for stabilizing aerosol pharmaceutical solution formulations containing glucocorticoids susceptible to oxidative degradation and use of a stabilizer selected between water and a mixture of water and organic acid selected between citric acid and tartaric acid are also described

Description

[0001] The invention relates to aerosol solution formulations containing glucocorticosteroids stabilized by adding water or a mixture of water and citric acid, avoiding corrosion of the elements of container under standard storage conditions. [0002] Particularly, the invention relates to certain 20-ketosteroids having an additional OH group in carbons 17 and / or 20 that have been found to be highly susceptible to chemical degradation when they are formulated as aerosol solution products. BACKGROUND OF THE INVENTION [0003] Glucocorticosteroids having a C-20 ketone and an OH group at the C-17 and / or 21 position with varying substituents, have many well-known therapeutic uses, especially based upon their anti-inflammatory activity. These types of steroids, glucocorticosteroids, and their pharmaceutical formulations are useful in the treatment of several diseases including bronchial disorders and inflammatory conditions. [0004] It is often desirable to deliver such steroids topically usi...

Claims

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Application Information

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IPC IPC(8): A61K9/12A61K31/57A61K31/573
CPCA61K9/0043A61K31/57A61K47/12A61K47/10A61K31/573A61P11/00A61P11/02A61P11/06A61P29/00
Inventor VEGA, JULIO CESARDE BONIS, FABIAN
Owner LAB PABLO CASSARA
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